Trends in Neurosciences
ReviewMitophagy and Alzheimer’s Disease: Cellular and Molecular Mechanisms
Section snippets
Early Clues That Mitochondria Are Central to AD
AD is the most common form of dementia and is characterized by a progression from episodic memory problems to severe cognitive decline and complete dependence of the patient on caregivers 1, 2, 3. The disease-defining histopathological abnormalities – extracellular deposits of Aβ and intraneuronal accumulation of hyperphosphorylated Tau (pTau) – ‘spread’ through the brain in a nonrandom manner with early pathology occurring in the entorhinal cortex and hippocampus 4, 5. However, the alterations
Mitochondria and Neuroplasticity
Mitochondria are organelles referred to as the ‘powerhouses’ of cells. Along with regulating calcium homeostasis and signaling to and from other organelles, mitochondria produce ATP by oxidative phosphorylation, in which electrons are passed through the electron transport chain from high-energy substrates to oxygen. Impaired mitochondrial function may lead to a reduction in cellular energy levels; concomitant leakage of electrons promotes the formation of reactive oxygen species (ROS), which
Mitophagy: Molecular Machinery and Regulatory Mechanisms
Autophagy is an evolutionarily conserved process in which cytoplasmic substrates are engulfed in autophagic vesicles, fused to lysosomes, and degraded. Autophagy is classified into various subgroups based on the mechanism of substrate delivery to the lysosome; these groups are macroautophagy, chaperone-mediated autophagy, and microautophagy 18, 20. We focus on macroautophagy (hereafter refer to as autophagy), in which engulfment by a double-membrane autophagosomal structure is followed by
Mitochondrial Dysfunction in AD
Studies in living AD patients and postmortem brain tissue have provided evidence that neurons in affected brain regions suffer impaired mitochondrial function. PET brain scans reveal decreased radiolabeled glucose uptake into neurons and biochemical analyses demonstrate reduced activity of mitochondrial enzymes involved in oxidative phosphorylation and the TCA cycle [6]. Recent findings suggest that mitochondrial biogenesis is impaired in AD as indicated by reduced levels of the transcriptional
Compromised Autophagy and Mitophagy in AD
Increasing evidence suggests that inhibition of the clearance of damaged mitochondria, along with concurrent increases in oxidative stress levels, results in the accumulation of dysfunctional neurons in AD. To be removed by mitophagy, the autophagosome containing the mitochondrion must fuse with a lysosome to form an autolysosome in which proteases degrade the mitochondrion (Figure 1A). Neurons exhibiting abnormal accumulation of autophagosomal vacuoles are a prominent feature in AD and their
Using iPSCs to Study Mitochondrial Function and Mitophagy in AD
The mitochondrial etiology of AD discussed here suggests that animal or cellular models with familial AD-associated genetic mutations, while of significant use, may not fully recapitulate important aspects of AD onset and progression. Studies using cells and tissue from human AD patients may better illustrate the nature and extent of mitophagy and mitochondrial dysfunction and iPSCs represent a useful tool for such studies. Since the discovery of iPSCs in 2006 by Yamanaka and colleagues [97],
Stimulating Mitophagy As an Approach to Delaying and Treating AD
Pharmacological agents and lifestyle interventions aimed at improving mitochondrial health and enhancing mitophagy have been evaluated in animal models and, in some cases, in mild cognitive impairment (MCI) or AD patients (Figure 3). Caloric restriction, intermitting fasting, and vigorous exercise are bioenergetic challenges that can promote neuroplasticity (synapse formation, hippocampal neurogenesis, and learning and memory) and bolster neuronal stress resistance 111, 112. Evidence from
Concluding Remarks
Significant progress has been made in ascertaining the causes of the devastating neurodegenerative disorder AD. The accumulation of dysfunctional mitochondria has emerged as a common feature of affected neurons in patients and animal models that may occur before discernible cognitive deficits. Experimental manipulations that impair mitophagy can enhance Aβ and pTau pathologies, while interventions that stimulate mitophagy can preserve synaptic plasticity and cognitive function. In addition,
Acknowledgments
The authors acknowledge the valuable work of the many investigators whose published articles they were unable to cite owing to space limitations. They thank Drs Emmette Hutchison and Krisztina Marosi for critical reading of the manuscript, Dr Nuo Sun for his comments and inputs, and Marc Raley for generation of the figures. This research was supported by the Intramural Research Program of the National Institute on Aging, including two NIA intralaboratory grants (2015-2016, 2016-2017 to
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